Developing systems capable of controlled and cell-targeted DNA delivery is essential to both basic science and clinical medicine. In the area of basic science, modulating a gene within a cell has the power to reveal or confirm the roles of specific components of signaling pathways and can lead to a mechanistic understanding of cell behavior, disease pathogenesis, and drug action. Alternatively, therapeutic strategies using DNA delivery are under development for inherited genetic disorders, cancer, and tissue regeneration. The successful application of DNA delivery for basic science and clinical medicine requires the ability to control the expression of target genes in the desired cell populations. Inspired by naturally occurring biomineralization processes, we have successfully developed DNA-doped carbonate nanocomposites on a cell culture-treated surface. By varying mineral compositions, the expression of genes in several cell lines can be modulated. Our preliminary studies have demonstrated the value of this approach. The programmable nature of mineral composites offers a great opportunity to tune delivery systems towards specific biological systems. In this R21 program, we aim to further explore this approach for future clinical and basic applications. This program will be accomplished through three specific aims: first, to establish a library of mineral solutions for delivering DNA to a variety of cell types by a high-throughput approach;second, to develop and optimize the process of biomineralization to program biodegradable polymer particles for controlled and cell-targeted DNA delivery in vivo;third, to test the effectiveness of programmable mesocomposites in a mouse tumor model by targeting DNA to dendritic cells (DCs) in vivo. The results derived from this application can be directly translated to a variety of clinical settings, including cancer gene therapy and DNA vaccines. Our inter-related three aims would demonstrate the value of programmable materials in complicated biological systems. This research program is to develop controlled and cell-targeted non-viral DNA delivery systems. The results can be directly translated to a variety of clinical applications including cancer gene therapy, DNA vaccines and tissue regenerations for the improvement of human health.